tbuckley/cabot-search huggingface dataset:
Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia
Authors: Liora M. Schultz, Anne Eaton, Christina Baggott, Jenna Rossoff, Snehit Prabhu, Amy K. Keating, Christa Krupski, Holly Pacenta, Christine L. Philips, Julie-An Talano, Amy Moskop, Susanne H.C. Baumeister, Gary Douglas Myers, Nicole A. Karras, Patrick A. Brown, Muna Qayed, Michelle Hermiston, Prakash Satwani, Rachel Wilcox, Cara A. Rabik, Vanessa A. Fabrizio, Vasant Chinnabhandar, Michael Kunicki, Sharon Mavroukakis, Emily Egeler, Yimei Li, Crystal L. Mackall, Kevin J. Curran, Michael R. Verneris, Theodore W. Laetsch, Heather Stefanski
Journal: Journal of Clinical Oncology (2022)

Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival.
Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47
Authors: Chong Yang, Rui Yokomori, Lee Hui Chua, Shi Hao Tan, Darren Qiancheng Tan, Kenichi Miharada, Takaomi Sanda, Toshio Suda
Journal: The Journal of Experimental Medicine (2022)

Intercellular mitochondria transfer is a biological phenomenon implicated in diverse biological processes. However, the physiological role of this phenomenon remains understudied between erythroblasts and their erythroblastic island (EBI) macrophage niche. To gain further insights into the mitochondria transfer functions, we infused EBI macrophages in vivo into mice subjected to different modes of anemic stresses. Interestingly, we observed the occurrence of mitochondria transfer events from the infused EBI macrophages to early stages of erythroblasts coupled with enhanced erythroid recovery. Single-cell RNA-sequencing analysis on erythroblasts receiving exogenous mitochondria revealed a subset of highly proliferative and metabolically active erythroid populations marked by high expression of CD47. Furthermore, CD47 or Sirpα blockade leads to a decline in both the occurrence of mitochondria transfer events and their mediated erythroid recovery. Hence, these data indicate a significant role of mitochondria transfer in the enhancement of erythroid recovery from stress through the alteration of the bioenergetic profiles via CD47–Sirpα interaction in the early stages of erythroblasts.
A Bivalent Omicron-Containing Booster Vaccine against Covid-19
Authors: Spyros Chalkias, Charles Harper, Keith Vrbicky, Stephen R. Walsh, Brandon Essink, Adam Brosz, Nichole McGhee, Joanne E. Tomassini, Xing Chen, Ying Chang, Andrea Sutherland, David C. Montefiori, Bethany Girard, Darin K. Edwards, Jing Feng, Honghong Zhou, Lindsey R. Baden, Jacqueline M. Miller, Rituparna Das
Journal: New England Journal of Medicine (2022)

The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known.In this ongoing, phase 2-3 study, we compared the 50-μg bivalent vaccine mRNA-1273.214 (25 μg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-μg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-μg) primary series and first booster (50-μg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose.Interim results are presented. Sequential groups of participants received 50 μg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-μg mRNA-1273.214 and 50-μg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster.The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065.).
A Century-long Journey From the Discovery of Insulin to the Implantation of Stem Cell–derived Islets
Authors: Adam Ramzy, Paul J Belmonte, Mitchell J S Braam, Shogo Ida, Emily M Wilts, Megan K Levings, Alireza Rezania, Timothy J Kieffer
Journal: Endocrine Reviews (2022)

Abstract For the past century, insulin injections have saved millions of lives, but glycemic instability is still a persistent challenge for people with diabetes, leading to tremendous morbidity and premature mortality. Research in the field of islet transplantation has demonstrated that replacing insulin-producing β cells can restore euglycemia comparable to individuals without diabetes. However, a short supply of cadaveric islet donors, the technically challenging process of isolating islets, and the requirement for chronic immune suppression have impeded widespread clinical adoption. Rather than relying on cadaveric cells, pluripotent stem cells could serve as a virtually unlimited supply of insulin-producing β cells. Protocols have been developed that mimic the normal in vivo development of the human pancreas to generate pancreatic progenitor cells in vitro. Ongoing investigations have yielded progressively more mature β-like cells in vitro that produce insulin but do not yet fully mimic healthy mature β cells. Alongside development of differentiation protocols, other work has provided insight into potential implantation sites for stem cell–derived islet cells including the subcutaneous space, portal vein, and omentum. To optimize implanted cell survival and function, development of immune modulation therapies is ongoing, including selection of immunomodulatory medications and genetic modification of implanted cells to evade immune responses. Further, macroencapsulation or microencapsulation devices could be used to contain and/or immunoprotect implanted cells from the immune response including by using 3-dimensional bioprinting to facilitate the process. Remarkably, ongoing clinical trials have now yielded the first patient relying on differentiated stem cells rather than syringes as their insulin replacement therapy.
Dabrafenib plus trametinib in patients with relapsed/refractory<i>BRAF</i>V600E mutation–positive hairy cell leukemia
Authors: Robert J. Kreitman, Philippe Moreau, Farhad Ravandi, Martin Hutchings, Anas Gazzah, Anne-Sophie Michallet, Zev A. Wainberg, Alexander Stein, Sascha Dietrich, Maja J. A. de Jonge, Wolfgang Willenbacher, Jacques De Grève, Evgeny Arons, Palanichamy Ilankumaran, Paul Burgess, Eduard Gasal, Vivek Subbiah
Journal: Blood (2022)

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.
Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Authors: Ellen Langille, Khalid N. Al-Zahrani, Zhibo Ma, Minggao Liang, Liis Uuskula-Reimand, Roderic Espin, Katie Teng, Ahmad Malik, Helga Bergholtz, Samah El Ghamrasni, Somaieh Afiuni-Zadeh, Ricky Tsai, Sana Alvi, Andrew Elia, YiQing Lü, Robin H. Oh, Katelyn J. Kozma, Daniel Trcka, Masahiro Narimatsu, Jeff C. Liu, Thomas Nguyen, Seda Barutcu, Sampath K. Loganathan, Rod Bremner, Gary D. Bader, Sean E. Egan, David W. Cescon, Therese Sørlie, Jeffrey L. Wrana, Hartland W. Jackson, Michael D. Wilson, Agnieszka K. Witkiewicz, Erik S. Knudsen, Miguel Angel Pujana, Geoffrey M. Wahl, Daniel Schramek
Journal: Cancer Discovery (2022)

Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent "long-tail" breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. This article is highlighted in the In This Issue feature, p. 2711.
Expert-level detection of pathologies from unannotated chest X-ray images via self-supervised learning
Authors: Ekin Tiu, Ellie Talius, Pujan Patel, Curtis P. Langlotz, Andrew Y. Ng, Pranav Rajpurkar
Journal: Nature Biomedical Engineering (2022)

In tasks involving the interpretation of medical images, suitably trained machine-learning models often exceed the performance of medical experts. Yet such a high-level of performance typically requires that the models be trained with relevant datasets that have been painstakingly annotated by experts. Here we show that a self-supervised model trained on chest X-ray images that lack explicit annotations performs pathology-classification tasks with accuracies comparable to those of radiologists. On an external validation dataset of chest X-rays, the self-supervised model outperformed a fully supervised model in the detection of three pathologies (out of eight), and the performance generalized to pathologies that were not explicitly annotated for model training, to multiple image-interpretation tasks and to datasets from multiple institutions.
Retraction: Characterization of Phosphoglycerate Kinase-1 Expression of Stromal Cells Derived from Tumor Microenvironment in Prostate Cancer Progression
Authors: Jianhua Wang, Gigi Ying, Jingchen Wang, Younghun Jung, Jian Lu, Jiang Zhu, Kenneth J. Pienta, Russell S. Taichman
Journal: Cancer Research (2022)

This article (1) has been retracted at the request of the authors. In Fig. 2A, a portion of the image showing α-SMA expression in CAFs was also used in Fig. 4A showing α-SMA expression in CAFControl. In addition, in Fig. 6B, portions of the p-p44/p42 Western blot were spliced together from separate blots, and lanes 3 to 4 were duplicated with lanes 5 to 6 in the p-AKT (473) Western blot. The authors apologize to the scientific community and deeply regret any inconveniences or challenges resulting from the publication and subsequent retraction of this article.A copy of this Retraction Notice was sent to the last known email addresses for 6 of the 6 authors. Three authors (J. Zhu, K.J. Pienta, R.S. Taichman) agreed to the retraction; 3 authors did not respond.
Multimodal Multidisciplinary Management of Patients with Moderate to Severe Pain in Knee Osteoarthritis: A Need to Meet Patient Expectations
Authors: Nicola Veronese, Cyrus Cooper, Olivier Bruyère, Nasser M. Al-Daghri, Jaime Branco, Etienne Cavalier, Sara Cheleschi, Mario Coelho da Silva Rosa, Philip G. Conaghan, Elaine M. Dennison, Maarten de Wit, Antonella Fioravanti, Nicholas R. Fuggle, Ida K. Haugen, Gabriel Herrero-Beaumont, Germain Honvo, Andrea Laslop, Radmila Matijevic, Alberto Migliore, Ali Mobasheri, Jean-Pierre Pelletier, María Concepción Prieto Yerro, Régis Pierre Radermecker, François Rannou, René Rizzoli, Jean-Yves Reginster
Journal: Drugs (2022)

Knee osteoarthritis (OA) is one of the most common and disabling medical conditions. In the case of moderate to severe pain, a single intervention may not be sufficient to allay symptoms and improve quality of life. Examples include first-line, background therapy with symptomatic slow-acting drugs for OA (SYSADOAs) or non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) performed a review of a multimodal/multicomponent approach for knee OA therapy. This strategy is a particularly appropriate solution for the management of patients affected by knee OA, including those with pain and dysfunction reaching various thresholds at the different joints. The multimodal/multicomponent approach should be based, firstly, on different combinations of non-pharmacological and pharmacological interventions. Potential pharmacological combinations include SYSADOAs and NSAIDs, NSAIDs and weak opioids, and intra-articular treatments with SYSADOAs/NSAIDs. Based on the available evidence, most combined treatments provide benefit beyond single agents for the improvement of pain and other symptoms typical of knee OA, although further high-quality studies are required. In this work, we have therefore provided new, patient-centered perspectives for the management of knee OA, based on the concept that a multimodal, multicomponent, multidisciplinary approach, applied not only to non-pharmacological treatments but also to a combination of the currently available pharmacological options, will better meet the needs and expectations of patients with knee OA, who may present with various phenotypes and trajectories.
Planetary respiratory health for asthma, rhinoconjunctivitis and eczema
Authors: Joan B. Soriano
Journal: European Respiratory Journal (2022)

Whatever the severity of any health condition, if the prevalence is in double digits globally, the implications for planetary health are tremendous. Should we consider the allergic triad of asthma, rhinoconjunctivitis and eczema (figure 1), periodic monitoring of their burden and determinants of change are fundamental for planning the existing efforts and forecasting the use of always limited resources. More descriptive and analytical epidemiology on asthma, hay fever and eczema are welcome https://bit.ly/3ISD1RQ
Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence
Authors: Li Pang, Oscar W.H. Yeung, Kevin T.P. Ng, Hui Liu, Jiye Zhu, Jiang Liu, Xinxiang Yang, Tao Ding, Wenqi Qiu, Yuewen Wang, T.L. Shirley Chiu, Zhiwei Chen, Chung-Mau Lo, Kwan Man
Journal: Cancer Research (2022)

Abstract Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress–induced HCC recurrence by attenuating postoperative immunosuppression. Significance: IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection.
Does increase of symptoms mean progression?
Authors: Christine Marosi, Tadeja Urbanic Purkart
Journal: Neuro-Oncology (2022)

Pooling data from several studies increases statistical power allowing analyses of special aspects with trends or marginal evidence within a single study. Patient-related outcomes (PROMS) and health-related quality of life (HRQoL) data are such topics, still often considered as “soft data”, since they measure perception of affected patients and not on reproducible measurements produced by a technical instrument. Nevertheless, HRQoL data are rated by the “end-consumers” of our neuro-oncological treatments. In this issue, Coomans et al.1, present pooled longitudinal data on HRQoL in glioma patients with the emphasis on HRQol during progression free survival. For this endeavor, within the CODAGLIO project (eg, COmbining clinical trial Datasets in GLIOma), patients whose HRQoL had been assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QlQ-C30)2 version 3.0 and the EORTC brain cancer specific QLQ-BN203,4 were included. These patients had participated in 15 previously published phase II or III studies for WHO grade 2 to four malignant gliomas, mostly EORTC led international trials, but also some national trials. Patients with at least a baseline assessment were included. The analysis stopped at assessment 4 with a completion rate of 57%, covering a follow up period of 8–40 months. A total of 5539 patients were included, 3381 men and 2155 women, the majority (n = 4665) with newly diagnosed gliomas. There was an elaborate statistical work-up of these data, allowing an delineation of different aspects. Each symptom is presented separately, as well as the timing of a clinically significant deterioration, the number of affected patients and the occurrence related to a specific treatment.